Figure 2. BDNF and depression — an example of the complexities of the molecular pathophysiology of depression.

a, Post-mortem data from depressed humans show that depression is associated with a decrease in the amount of BDNF in the hippocampus³³ and an increase (of similar magnitude) in the NAc²⁵, an example of the regional specificity of depression-related neuroplastic changes. b, Neuronal secretion of BDNF occurs through regulated (activity-dependent) and constitutive secretory pathways. Regulated secretion is modulated by the interactions of proteins in the Golgi apparatus with the pro-domain of BDNF, the site of a single-nucleotide polymorphism (G196A) in humans that results in the substitution of valine at amino-acid residue 66 with methionine. c, The Met-66-containing BDNF variant has impaired intracellular trafficking. Met-66 BDNF is not properly sorted within the cell, causing it to be distributed throughout the cell body outside of vesicles⁴². In addition, less BDNF is secreted from the nerve terminal. d, Knock-in mice that homozygously express Met-66 BDNF⁴¹ have normal responses in the forced-swim test²⁵, but these mice show more anxiety-like behaviour⁴¹ and greater resilience to behavioural and molecular changes after social defeat²⁵, implicating this BDNF polymorphism in the pathophysiology of psychological disorders that are influenced by stressful life events.